Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension: Focus on Phosphodiesterase Inhibitors

Abstract

Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated with significant right ventricular dysfunction. In approximately 20% of patients with HFpEF, "precapillary" alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH), pertaining to a poor prognosis. Current data indicate that pulmonary vasculopathy may be at least partially reversible and thus serves as a therapeutic target in HFpEF. Pulmonary vascular targeted therapies, including phosphodiesterase (PDE) inhibitors, may have a valuable role in the management of patients with PH-HFpEF. In studies of Cpc-PH and HFpEF, PDE type 5 inhibitors were effective in long-term follow-up, decreasing pulmonary artery pressure and improving RV contractility, whereas studies of Ipc-PH did not show any benefit. Randomized trials are essential to elucidate the actual value of PDE inhibition in selected patients with PH-HFpEF, especially in those with invasively confirmed Cpc-PH who are most likely to benefit from such treatment.

Keywords: PDE inhibitors; diastolic dysfunction; heart failure with preserved ejection fraction; phosphodiesterase; pulmonary hypertension.

Figure 1

Stages of pulmonary hypertension in HFpEF. A chronic increase in mean left atrial (LA) pressure causes an increase in pulmonary artery (PA) pressure (pulmonary hypertension, PH), leading to passive remodeling in pulmonary venule and capillaries and isolated postcapillary PH (Ipc-PH). In approximately 20% of patients with HFpEF, the reactive “precapillary” alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH). Ipc-PH is associated with a decrease in pulmonary arterial capacitance (PAC) and mild adaptive changes of the right ventricle (RV). On the other hand, Cpc-PH leads to an increase in pulmonary vascular resistance (PVR), PA-RV uncoupling, and is associated with a marked maladaptive RV remodeling with RV systolic dysfunction and dilation, tricuspid regurgitation, and increase in central venous pressure (CVP). Increased CVP results in a reduction of sodium (Na⁺) excretion and fluid retention, and a further increase in LA pressure. With RV dilatation and CVP increase, shifting of the interventricular septum (IVS) to the left occurs, resulting in an impaired left ventricular filling. DPG indicates diastolic pulmonary gradient; mPAP, mean pulmonary artery pressure; PA, pulmonary artery, PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary pressure gradient.

Figure 2

Cyclic nucleotide signaling in cardiomyocyte. Nitric oxide and natriuretic peptide receptor (NPR) activate soluble (sGC) and particulate guanylate cyclases (pGC), respectively, resulting in production of cyclic guanosine monophosphate (cGMP) and activation of protein kinase G (PKG). PKG phosphorylates numerous targets within myocyte. PKG-mediated phosphorylation (P) of phospholamban (PLB) activates sarcoplasmic–endoplasmic reticulum calcium ions (Ca²⁺)-ATPase pump (SERCA) and increases Ca²⁺ uptake into sarcoplasmic reticulum (SR); phosphorylation of troponin I (Tn I) reduces myofilament Ca²⁺ sensitivity increasing lusitropy. PKG-mediated phosphorylation of titin reduces cardiomyocyte stiffness, whereas PKG-mediated phosphorylation of L-type channels decreases Ca²⁺ influx, possessing a negative inotropic effect. Activation of β₁-adrenergic receptors by epinephrine activates adenylate cyclase (AC), increasing the level of cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA). High PKA activity leads to a positive inotropic effect due to phosphorylation of the L-type Ca²⁺ channel and the ryanodine receptor (not shown), increasing the systolic Ca²⁺ influx. PKA activation also possesses lusitropic effects through phosphorylation of the same targets as PKG-Tn I and PLB. PKA signaling mediates cardiac hypertrophy by increasing Ca²⁺ and calcineurin activation, as well as by increasing transcription. High cGMP and PKG levels promote negative inotropic effects and counteract PKA-mediated cardiac prohypertrophic signaling. cGMP also affects cAMP levels by inversely modulating PDE3. Phosphodiesterase cleaves cGMP, and PDE5 and PDE9 inhibitors increase cGMP levels. PDE5 primarily cleaves cGMP from the nitric oxide-rGC axis, while PDE9 cleaves cGMP from the natriuretic peptide-rGC axis. ATP indicates adenosine triphosphate; GTP, guanosine triphosphate; Tm, tropomyosin.